Molecular and computational tools for investigating genomic imprinting

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Over the last decade biological research has benefitted tremendously from deployment of high-throughput genomic technologies. Our ability to quickly and cheaply sequence all of the DNA in our cells has made it easier than ever to link variation to physical traits. Since DNA is transmitted through generations, it is traditionally regarded as the basic means of heritability. Epigenetics is the study of heritability that is based on mechanisms that do not involve DNA sequence. This typically involves chemical modifications to the DNA or the proteins associated with DNA, and manifests as observable traits by regulating gene expression. Although several tools exist for mapping the chemical modifications thought to underlie epigenetics, understanding how these features cause heritable phenotypic effects in a high-throughput manner will require development of new technologies and methods. Our research program focuses on genomic imprinting - one of the best characterized examples of epigenetics - where some genes are silenced depending on whether they were inherited from mother or father. Two copies of each gene are thought to ensure that a deleterious mutation in one gene is masked by the “healthy” copy inherited from the other parent. Why would a species evolve a mechanism to silence specific genes, and always in a parent-of-origin manner? This question has fuelled over 30 years of research that culminated in just over 100 known imprinted genes in humans and mouse. We recently published a high-throughput method that recapitulated 25 years of discovery in a single experiment. We have since improved on the method and used it to investigate tissue-specific imprinting; work that has culminated in strong support for a specific evolutionary theory explaining the origins of imprinting. What has become obvious from these efforts is that simply generating maps of imprinted genes is insufficient, and that we need to know when specific genes became imprinted in their evolutionary history and what the functions of imprinted genes are. We are tackling these questions head-on, by extending our knowledge of the breadth of genomic imprinting across species, development, and anatomy, we will be able to infer how and why the phenomenon evolved. It will also enable us to directly ask what are the consequences of monoallelic expression in vertebrates. This work and the tools we are developing will have many applications in evolutionary biology, health sciences, and in investigating the potentially large contribution of epigenetics in shaping the diversity of life. The bulk of the NSERC support requested here is for training HQP.